1144
J. Org. Chem. 1990,55,1144-1146
the enantioselectivity of the allyl- and crotylborations of ol,&unsaturated aldehydes is poor (62-74% ee for (E)decenal and 1-31? and the masked acetylene unit of 8 can be viewed as a synthetic equivalent of both E and 2 olefms in the reaction products. 2-Decynal, too, is a poor allylboration substrate: the reactions with 1-3 under standard conditions provide 9-11 with enantiomericexcesses of only 72%, 72%, and 58%, respectively. It is thus significant that the reactions of 8 with (RJ0-1, (RJ0-2,and (R,R)-3 (toluene, -78 "C,4-A sieues) followed by oxidatiue decomplexation (Fe(NO,),,EtOH, 23 "C)prouide 91° (92% ee), 10'O (96% ee; 973 anti to syn), and II'O (86% ee; 973 syn to anti) in 8545% yield. Here again, the absolute stereochemical outcome is the same with both 2-decynal and the dicobalt hexacarbonyl complex 8.'l
boration of p-nitrohenzaldehyde with 1proceeds with the same enantioselectivity as PhCH0.'2 The increased enantioselectivityalso does not appear to he due to a steric effect, since the bulky metal carbonyl units can be positioned away from the allyl group in both the favored and disfavored transition states as indicated below for the reaction of 4. Moreover, in the asymmetric allylborations of hindered substrates (e.g., pivalaldehyde) with 2 and 3, enantioselectivity in fact decreases relative to less sterically demanding substrates? Rather, we speculate that the stereochemically preferred transition state is stabilized by a favorable dipoledipole interaction between the tartrate ester and the metal carbonyl unit as indicated in the three-dimensional structure presented below for 4.lCJ3 Such interactions are possible only in the favored transition state.
I R1
,amred M " Y l m 11ae n"
8
These examples clearly demonstrate that the enantioselectivity of the asymmetric allylborations of aryl and propargylic aldehydes may be significantly improved by using appropriate metal carbonyl derivatives. The origin of this effect, however, cannot be explained by invoking previously established principles of metal carbonyl chemistry.'" For example, while the Cr(CO), unit of 4 is well known to have a significant inductive effect, comparable to a p-N02 substituent," this electronic effect is not responsible for the increased enantioselectivity: the allyl(IO) SstiifSaOry 'HNMR,IR,rnasll spectra, and C, H analytical data were obtained for this compound. (11) The relative and absolute sterenstructures of 9-11 have been assigned by hydrogenation of each to the corresponding tridecanols that have been correlated with materials prepared by the Sharpless asymmetric epoxidatian reactions (ref 8s,b).
&slawred
In summary, we have shown that the enantioselectivity of the asymmetric allylborations of certain unsaturated aldehydes is significantly improved by using metal carbonyl derivatives as substrates. These results are also of considerable interest since the reaction products are chiral organometallic complexes that are potential substrates for a range of stereoselectivetransition metal mediated organic reactions, a line of investigation that we are actively pursuing.
Acknowledgment. This research was supported by a grant from the National Institute of General Medical Sciences (GM 38436). (12) 7he asymmetric allylborationsof pa-substituted benzaldehydes INO.. Br. H. Me. OMel o m e d with 7 ~ F 7 2 %ae usinn " I in THI? b u s h . W. 8:Hwiooha. L. K..ukublished. (13) (a) For evideneebupponing the indicated transition-state conformation of the diorsborolane unit: b u s h . W. R.; Banfi, L. J. Am. Chem. Snr. 1988. 110. 3979. Ibl Additional allvlborstion results have rationalizedby h&ki&dipI&& htsraetiohs:Roush, W. R; Hoong, L.K.;Palmer, M. A. J.; Straub, J. A,; Palkowitz, A. D. J. Org. Chen.. submitted.
.
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Enantiospecific Synthesis of an Aziridinobenzoazocinone, an Advanced Intermediate Containing the Core Nucleus of FR900482 and FK973 Robert J. Jones and Henry Rapoport: Department of Chemistry, University of California, Berkeley, California 94720 Received December 4, I989 Summary: A route to the enantiospecificsynthesis of the aziridinobenzohexahydroazocineketone 14, containing the core nucleus of F R W 2 and FK973, has been developed. It consists of coupling the two key intermediates, sulfonanilide 7 and methyl (2S,3S)-2,3-aziridino-4-hydroxybutyrate 12, prepared from vinylglycine, followed by cyclization to the azocinone 14. In 1987 the isolation was reported of a potent antineoplastic agent from cultures of Streptomyces sandaensis
No. 6897; it was designated FR900482, 1.l4 This unique compound exists in two diastereomeric forms, A and B, due to the hydroxylamine hemiketal functionality. The A form is favored in neutral and acidic media possibly due (1) Uchida, I.; T h e , S.; Kay& Am. Chem. Soc. 1987,109,4108.
K; Kiyoto, S.;Hashirnoto, M. J.
(2) Iwami.M.:Kivoto.S.:Terano.R:KohsalraM.:Aaki.H.:Imanslra . . . . . . H.J..Antibiot. i9Si. 40,589. (3) Kiyoto, S.;Shibata. T.; Yamaahita, M.; Komori, T.; Okuhars, M.;
Terano,H.;Kohsaka,M.;Aoki,H.;Imanelra,H.J.Antibiot.1987,40.594.
0022-3263/90/1955-1144$02.50/00 1990 American Chemical Society
Communications
J. Org. Chem., Vol. 55, No. 4,1990 1145 Scheme I
HO$N02
-
MOMO$N , 02
H /Pd/C
MOMCI
0
0
K2C03
MOM$NH2
0
PhSO 92%CI
2_
94%
MOM$NHSO2Ph 0
1
97%
C02R
C02CH3
3 R=H 4 R=CH3
C02CH3 6
5
CH3O2C~NHR~
~
-
C02CH3
1C H03 0 2~C y N H B 0 c
7
I.MSCVEt3N 2. TFA
U
11
10
0 R=CBZ
12
9 R=BOC
Ph602
Phd02
14
13
to hydrogen bonding between the aziridine NH and the bridging oxygen. The B form is predominant in the triacetate 2, FK973, which was selected for biological s ~ r e e n i n g .The ~ ~ ~diastereomers presumably interconvert through the tautomeric tricyclic keto form C.' Ro
,OCO"2
RO
,OCO"2
0""
-
NR OHC
OHC
NR
B
A
1 R=H 2 R=Ac
H0'
C
The triacetate FK973,2, has displayed a very promising biological profile. Showing activity against various transplanted human and murine tumors, FK973 is 3 times more potent than mitomycin C and significantly less It has been proposed that FK973 is gradually activated in the cytoplasm of cells and the activated FK973 forms interstrand DNA-DNA and DNA-protein crosslink~.'*~ It does not cause oxidative scission of singlestranded DNA.'s8 Due to their potent antineoplastic activity and unique structures, FR900482 and FK973 are attractive candidates for synthesi~.~ (4)Shimomura, K.; Hirai, 0.; Mizota, T.; Matsumoto, S.; Mori, J.; Shibayama, F.; Kikuchi, H. J. Antibiot. 1987,40,600. (5)Hirai, 0.;Shimomura, K.; Mizota, T.; Matsumoto, S.;Mori, J.; Kikuchi, H. J. Antibiot. 1987,40,607. (6)Shimomura, K.; Manda, T.; Mukumoto, S.; Masuda, K.; Nakamura, T.; Mizota, T.; Mataumoto, S.;Nishigaki, F.; Oku, T.; Mori, J.; Shibayama, F. Cancer Res. 1988,48,1116. (7)Masuda, K.; Nakamura, T.; Mizota, T.; Mori, J.; Shimomura, K. Cancer Res. 1988,48,5172. (8)Masuda, K.; Nakamura, T.; Shimomura, K.; Shibata, T.; Terano, H.;Kohsaka, M. J. Antibiot. 1988,41, 1497. (9)Yasuda, N.; Williams, R. M. Tetrahedron Lett. 1989,30, 3397.
Our starting material for the synthesis of the aromatic portion of FR900482 is the nitrophenol 3.1° The methyl ester 4 was formed under Fischer esterification conditions with methanol and sulfuric acid in 93% yie1d.l' Phenol 4 was then converted almost quantitatively into the methoxymethyl ether 5, mp 60-61 "C, using potassium carbonate and chloromethyl methyl ether in acetone (see Scheme I). The nitro group of 5 was catalytically reduced to afford the aniline 6, mp 99-100 "C, in 94% yield. Reacting this aniline derivative with benzenesulfonyl chloride, pyridine, and DMAP in acetonitrile gave a 92% yield of the protected aniline 7,12mp 145.5-146.5 "C. The precursor to the aliphatic portion of FR900482 was the optically pure CBZ epoxide 8.13 The CBZ group was exchanged for a BOC to afford epoxide 9.14 Opening BOC epoxide 9 with allyl alcohol and catalytic 60% aqueous HC10416gave a 40% yield of allyl ether 10 with the BOC moiety intact. Allyl ether 10 was then converted to the protected aziridine 11 in 84% overall yield by mesylation of the alcohol (MsC1,200 mol % ; triethylamine, 200 mol 5%); removal of the BOC group (TFA); aziridine formation and protection as its 9-phenylfluoren-9-yl (PhF1)l6derivative (K3P04,300 mol %; Pb(NO&, 100 mol %; PhFlBr, 115 mol %). Removal of the allyl ether was accomplished in two steps. First the double bond was isomerized to the stable vinyl ether with Wilkison's catalyst (RhCl(PPh3)3, 10 mol %; DBU, 10 mol %; EtOH1.l' Subsequent hy~~
~
~~
~
(10)Nitrophenol 3 was prepared in two steps and 49% yield from commerically available 3,5-dinitrotoluic acid as described by Nielson, 0. B. T.; Bruun, H.; Bretting, C.; Feit, P. W. J. Med. Chem. 1975,18, 41. (11)Satisfactory elemental analyses and spectral data were obtained for all new compounds. (12)7: 'H NMR (CDC13)6 2.00 (8, 3 H, ArCH3), 3.43 (s, 3 H, OCHJ, 3.86 (s. 3 H. C0,CHd. 5.19 (8. 2 H.OCHOO).7.14 (s. 1 H. ArH). 7.45 (d. 2 H, J'= 7.8 HzrArH), 7.55($, 2 H, J = i . 5 H z , AIH), 7.60 (d,'l H,j = 1.16Hz, ArH), 7.76 (m, 2 H, ArH); '% NMR (CDCl,) 6 10.69,52.25,56.28, 94.60,112.56,119.41,127.23, 127.44,128.90,129.09,133.13,135.29, 139.31, 155.51, 166.23. (13)This epoxide was constructed from L-methionine in five steps and 41% overall yield following the procedure of Shew, K. J.; Luly, J. R.; Rapoport, H. J . Org. Chem. 1985,50,4515. (14)Yields varied from 70 to 90% by carrying out the hydrogenolysis in methanol with hydrogen at atmospheric pressure over 10% Pd/C in the presence of 250 mol % of (BOC),O Truong, T.; Rapoport, H., manuscript in preparation. (15)Fieser, L.F.; Goto, T. J. Am. Chem. SOC.1960,82,1693. (16)Christie, B. D.; Rapoport, H. J. Org. Chem. 1985,50,1239.
J. Org. Chem. 1990,55. 1146-1147
1146
drolysis of the vinyl ether was more difficult than expected, requiring TsOH (15 mol %) and 18 h, and the alcohol 1218 was obtained in 55% yield, along with a significant amount of phenylfluorenyl alcohol from solvolysis of the product or intermediate. Mitsunobu couplinglg (PPh3, 100 mol %; DMAD, 100 mol 5% ; THF) of benzenesulfonamide 7 and aziridino alcohol 12 afforded the coupled (phenylsulfony1)anilide13, mp 81-84 "C, as a mixture of conformational isomers in 87% yield. At this stage, we anticipated that the para ester group would sufficiently increase the acidity of the tolyl methyl protons of 13 to permit deprotonation and condensation with the aziridino methyl ester. Although such intramolecular condensations to form eight-membered rings are generally quite poor processes, the severe conformational constraints imposed by the fused benzene and aziridine rings were expected to overcome this barrier. In (17) Core? E. J.; Suggs, J. W. J. Org. Chem. 1973, 38, 3224. (18) 12: H NMR (CDC13) 6 1.74 (q, 1 H, J = 6.6 Hz, H ), 2.52 (d, 1 H , J = 6.6 Hz, He), 3.56 (b d, 1 H , J = 4.5 Hz,H ), 3.72 (8, 3 COZCH,), 7.14-7.49 (rn, 11 H, ArH), 7.71 (rn, 2 H, ArH); 136NMR 6 37.36 (1),40.39 (l),51.75 (3),59.83 (2), 75.15, 119.81 (l),125.26 (l),125.95 (l),126.57 (l), 126.92 (l),127.24 (l),127.75 (l),128.0 (l),128.56 (l),128.74 (l),139.60, 141.11, 142.23, 144.72, 147.79, 169.71. (19) Mitaunobo, 0. Synthesis 1981, 1. A similar application to aliphatic amines has just appeared Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D., Jr.; Weinreb, S. M. Tetrahedron 1989, 30, 5709.
8,
the event, treatment of the Mitsunobu product 13 with KHMDS (500 mol %, THF, -10 to 5 "C) afforded the ketone 14,20mp 220-222 "C, in 52% yield. This completes the synthesis of the core (3S,4S)-3,4-aziridinobenzo[l,2blhexahydroazocine nucleus. To complete the synthesis of FR900482, introduction of the carbamoylmethyl group and the remaining functional group manipulations with ketone 14 are being pursued. Acknowledgment. Michael Carrasco, President's Undergraduate Fellow, provided valuable assistance in the preparation of intermediates. Supplementary Material Available: Complete experimental details and 'H and 13C NMR data for numbered compounds in the synthetic sequence (4,5,6, 7, 10 and its mesylate, 11, 12,13, 14) (7 pages). Ordering information is given on any current masthead page. (20) 14: 'H NMR (CDC13)6 1.96 (d, 1 H, J = 6.6 Hz, Ha), 2.47 (9, 1
H,J = 3.3 Hz, H#), 3.50 (d, 1 H, J = 14.3 Hz, H7),3.51 (d, 1 H, J = 18.1 Hz,HBn),3.56 ( s , 3 H, OCH3),3.79 (d, 1 H, J = 18.0 Hz, H B ~ )3.93 , (s, 3 H,CO,CH,), 4.29 (dd, 1 H, J = 3.4, 14.3 Hz, HJ, 5.29 (d, 1 H, J = 6.6 Hz,CH,), 5.46 (d, 1 H, J = 6.6 Hz,CHJ, 6.62-7.92 (m,20 H, ArH); 13C NMR (CDCl,) S 42.37 (l),42.53 (2), 45.34 (l),47.97 (2), 52.36 (3), 56.62 (3), 75.43, 95.10 (2), 115.25 (l),120.10 (l),120.31 (l),121.44 (l),124.91 (l),126.35 (l),126.44 (l),127.01 (l),127.18 (l),127.77 (l),127.95 (11, 127.99 (l),128.74 (l), 129.04 (l), 129.26 (l),129.42 (l), 133.32 (11, 136.35, 138.03, 139.13, 140.47, 142.07, 142.14, 142.55, 147.74, 154.31, 165.79, 204.13.
Reaction of Trithiolanes with Dihalocarbenes under Phase-Transfer Catalysis. A Convenient Synthesis of Trithiocarbonates and Thionocarbonates Tirthankar Ghosh Department of Chemistry, Princeton University, Princeton, New Jersey 08544 Received October 9,1989
Summary: The reaction of trithiolanes with both dichloroand dibromocarbene under phase-transfer catalysis has been studied in detail. The primary product is the trithiocarbonate, which undergoes further reaction to give the thionocarbonates. A mechanism for this reaction is discussed. Recently we reported on the oxidation of norbornane trithiolanes with a variety of reagents.l This study indicated that simple norbornane trithiolanes have the potential to serve as good models for investigating trisulfide chemistry. Here we describe the reaction of trithiolanes with dihalocarbenes. Although we have been unable to find any example in the literature on the reactivity of trithiolanes (or trisulfides for that matter) with dihalocarbenes, there are quite a few reports on the reaction with disulfides. In the earliest study of the reaction of disulfides with carbenes, Searles and Wann found that dichlorocarbene led to (dichloromethy1)alkyl disulfides and alkenes (eq 1).2 (CH,),CSSC(CH,), + CC12 (CH3)3CSSCHC12+ CH2=C(CH3)2 (1) Aryl disulfides on the other hand do not react with di-
-
(1) Ghosh, T.;Bartlett, P. D. J.Am. Chem. SOC.1988,110,7499-7506. (2) Searles, S., Jr.; Wann, R. E. Tetrahedron Lett. 1965, 2899-2902.
Table I. Ratio of 2 and 3 with Time time. h 213 1. 90 0.17 2.9 52 1 2.9 24 7 2.3 16 17 2.3 16
chlorocarbene.3 Recently dichlorocarbene has been shown to act as both as an oxidizing and reducing agent for organosulfur compounds under phase-transfer c a t a l y s i ~ . ~ * ~ With this information in hand the following study was undertaken. Heating a mixture of exo-3,4,5-trithiatricyclo[5.2.1.02.6]decane(1): excess NaOH and benzyltriethylammonium chloride (TEBAC) in CHC1, at reflux gave a 60% yield of exo-3,5-dithia-4-o~otricyclo[5.2.l.O~~~]decane (2)7as the only product. If the reaction is carried out at
1
2
(3) Field, L.; Banks, C. H. J. Org. Chem. 1975, 40, 2774-2779. (4) Soysa, D. S. H.; Weber, W. P. Tetrahedron Lett. 1978,1969-1970. (5) Evans, S. H., Jr.; Dyer, J. C. J. Org. Chem. 1980,45, 5350-5355. (6) Bartlett, P. D.; Ghosh, T. J. Org. Chem. 1987, 52, 4937-4943.
0022-3263f 9011955-1146$02.50/0 0 1990 American Chemical Society
